Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis
Abstract Background Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-020-01806-5 |
| _version_ | 1818730817507033088 |
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| author | Jianyong Sun Yanlu Xiong Kuo Jiang Bo Xin Tongtong Jiang Renji Wei Yuankang Zou Hong Tan Tao Jiang Angang Yang Lintao Jia Lei Wang |
| author_facet | Jianyong Sun Yanlu Xiong Kuo Jiang Bo Xin Tongtong Jiang Renji Wei Yuankang Zou Hong Tan Tao Jiang Angang Yang Lintao Jia Lei Wang |
| author_sort | Jianyong Sun |
| collection | DOAJ |
| description | Abstract Background Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive. Methods Firstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples. Results CASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients. Conclusions HIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC. |
| first_indexed | 2024-12-17T23:07:49Z |
| format | Article |
| id | doaj.art-858e25555f3c45b8a2ed595ce01719d8 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-17T23:07:49Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-858e25555f3c45b8a2ed595ce01719d82022-12-21T21:29:12ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662021-01-0140111410.1186/s13046-020-01806-5Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axisJianyong Sun0Yanlu Xiong1Kuo Jiang2Bo Xin3Tongtong Jiang4Renji Wei5Yuankang Zou6Hong Tan7Tao Jiang8Angang Yang9Lintao Jia10Lei Wang11State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityDepartment of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical UniversityDepartment of Spine Surgery, Honghui Hospital, Xi’an Jiaotong UniversityDepartment of Oncology, The 960th Hospital of PLAState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityThe Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, Department of Occupational and Environmental Health, Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityDepartment of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical UniversityDepartment of Immunology, Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityState Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityAbstract Background Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive. Methods Firstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples. Results CASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients. Conclusions HIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.https://doi.org/10.1186/s13046-020-01806-5Long noncoding RNACASC15SOX4Non-small cell lung cancerHypoxia signaling |
| spellingShingle | Jianyong Sun Yanlu Xiong Kuo Jiang Bo Xin Tongtong Jiang Renji Wei Yuankang Zou Hong Tan Tao Jiang Angang Yang Lintao Jia Lei Wang Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis Journal of Experimental & Clinical Cancer Research Long noncoding RNA CASC15 SOX4 Non-small cell lung cancer Hypoxia signaling |
| title | Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis |
| title_full | Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis |
| title_fullStr | Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis |
| title_full_unstemmed | Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis |
| title_short | Hypoxia-sensitive long noncoding RNA CASC15 promotes lung tumorigenesis by regulating the SOX4/β-catenin axis |
| title_sort | hypoxia sensitive long noncoding rna casc15 promotes lung tumorigenesis by regulating the sox4 β catenin axis |
| topic | Long noncoding RNA CASC15 SOX4 Non-small cell lung cancer Hypoxia signaling |
| url | https://doi.org/10.1186/s13046-020-01806-5 |
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